Uterine cancer is the most common type of gynecologic cancer. The frequency of uterine leiomyosarcoma development is low, and it accounts 2% to 5% of cases of uterine body cancer. Uterine leiomyosarcoma develops more often in the muscle layer of the uterine body than in the uterine cervix. The myometrium is composed of smooth muscle. Uterine leiomyoma is a benign tumor that develops in the myometrium, and uterine leiomyosarcoma is a malignant tumor. Differentiation of uterine leiomyoma from uterine leiomyosarcoma was very difficult. In general, tissue has been sampled via surgery, and whether or not a tumor was uterine leiomyoma or uterine leiomyosarcoma has been identified via microscopic cell analysis. Uterine leiomyosarcoma is highly atypical and often allows proliferation of tumor cells that occasionally become gigantic. In some cases, such tumors do not substantially show cellular atypism, and the presence or absence of cellular atypism would not serve as a definite discriminant. Uterine leiomyoma is differentiated from uterine leiomyosarcoma based on the occurrence of coagulative necrosis and the enlargement of an image representing cell division. When a cell density is high, in principle, a tumor is identified to be uterine leiomyosarcoma if 10 or more cell divisions are observed in a 10× wide-field view. The tumor is identified to be uterine leiomyosarcoma if 5 or more atypisms are observed in the tumor cell in a 10× wide-field view. In practice, uterine leiomyoma has been differentiated from uterine leiomyosarcoma based on the degree of cellular atypism, cell density, the number of cell divisions, tumor necrosis, and the bleeding of tumor. Such differentiation was mainly made by observing tissue morphology microscopically or visually. However, expert skills are required for such differentiation, and such differentiation is not always accurate.
In the past, the present inventors reported that uterine leiomyosarcoma was observed in 6-month or older female mice each lacking an immunoprotease component; i.e., low molecular mass polypeptide 2 (LMP2), and that the incidence thereof in 12-month-olds would account for about 35% of all LMP2-lacking female mice (see Van Kaer L. et al., 1994, Immunity, 1, 533-541 and Hayashi T. et al., 2002, Cancer Res., 62, 24-27). LMP2 functions in a tissue-specific manner and plays an essential role in MHC class I-mediated tumor rejection by CTLs (see Van Kaer L. et al., 1994, Immunity, 1, 533-541).
Thus, lack of LMP2 was deduced to serve as a factor for developing uterine leiomyosarcoma by means of certain functions. The 26S proteasome comprising LMP2, however, is involved in a complex manner with activation of a transcription regulator or a cell-cycle regulator, production of a peptide antigen of an MHC class I molecule, and the like, and a direct correlation between LMP2 and development of uterine leiomyosarcoma was unknown. The way that functions of the 26S proteasome would change and the way that transcription and expression of LMP2 would change upon development of uterine leiomyosarcoma were unknown.